Rev Psychiatr Neurosci 2007;32(2)
© 2007 Canadian Medical Association
Folate and depression—a neglected problem
Simon N. Young, PhD
Co-editor-in-chief, Journal of Psychiatry and Neuroscience, and Department of Psychiatry, McGill University, Montréal, Que.
Researchers are not immune to fashion. A wealth of data go-
ing back several decades relating serotonin function to the
regulation of mood and the current emphasis on genetics in
biological psychiatry research have resulted in an increasing
number of studies relating various polymorphisms of sero-
tonin-related genes to various types of psychopathology. The
assumption behind these studies is that the polymorphisms
may alter serotonin function and therefore alter susceptibility
to depressed mood or other symptoms. This line of research
is important from a theoretical perspective but has fewer
practical implications (except possibly in predicting response
to drugs); practical methods to alter genes in depression pa-
tients are a long way in the future. The current explosion of
work on serotonin-related polymorphisms is in sharp con-
trast to the much smaller number of recent studies on an
entirely reversible environmental factor known to lower sero-
tonin synthesis—folate deficiency. The purpose of this editor-
ial is to draw attention to what is known about the epidemi-
ology and biochemical and clinical effects of folate deficiency,
to point out what studies are needed and to consider the re-
cent recommendation that patients with depression should
be treated with 2 mg of folic acid.1
Many studies, going back to the 1960s, show an elevated
incidence of folate deficiency in patients with depression.2
Studies vary depending on the criteria used to define folate
deficiency, but often, about one-third of depression patients
were deficient. Given that depression is often accompanied
by decreased appetite and weight loss, the high incidence of
folate deficiency in depression patients is not surprising.
However, there is some evidence, though not conclusive, that
folate deficiency may be involved in the etiology of depres-
sion in a minority of patients. Alternatively, depressed mood
may decrease appetite, lower folate levels and thereby help
to prevent recovery from depression. A recent review and
metaanalysis looked at the results from the limited number
of studies that investigated the effect of giving folate to de-
pression patients and concluded that “there is some evidence
that augmentation of antidepressant treatment with folate
may improve patient outcome.”3Whether the putative bene-
ficial effect of folate is limited to those with folate deficiency
is not clear.1,3
If folate deficiency can contribute to depressed mood and
folate supplementation is beneficial in patients, a plausible
mechanism implicates serotonin. In most,4–8but not all,9,10
studies on patients with neuropsychiatric disorders, folate
deficiency was associated with low levels of the serotonin
metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the cere-
brospinal fluid (CSF). In one study, supplementation with fo-
late restored CSF 5-HIAA levels to normal.8There is also a
decrease in serotonin synthesis in patients with 5,10-methyl-
enetetrahydrofolate reductase (MTHFR) deficiency, a disor-
der of folate metabolism.11,12While the mechanism relating
folate deficiency to low serotonin is not known, it may in-
volve S-adenosylmethionine (SAMe). SAMe is a major
methyl donor formed from methionine. Folate is involved in
a cycle that regenerates methionine from homocysteine after
SAMe is demethylated to S-adenosylhomocysteine, with sub-
sequent conversion to homocysteine. Folate deficiency
decreases SAMe in the rat brain.13In humans, SAMe is an an-
tidepressant14,15and increases CSF 5-HIAA levels.16Thus,
there is some consistency in what is known about the interre-
lations of folate, SAMe and depression.
There is an important need for additional studies on folate
and depression, the most pressing of which is larger studies
on the ability of folate to potentiate the action of standard
antidepressant therapies. Additional issues that need to be
addressed are the dosage of folate needed to get the maxi-
mum effect and the possibility that the response may differ
in different subgroups, such as those with and without overt
folate deficiency. Meanwhile, how should clinicians act, con-
sidering what we currently know? In particular, should all
depression patients be given folate supplements, and if so,
how much? Is there no need for supplements in countries
with mandatory or voluntary fortification of foods with
Correspondence to: Dr. Simon N. Young, Department of Psychiatry, McGill University, 1033 Pine Ave. W., Montréal QC H3A 1A1; fax
514 398-4370; email@example.com
J Psychiatry Neurosci 2007;32(2):80-2.
Medical subject headings: folic acid; serotonin; depression; food, fortified.
J Psychiatry Neurosci 2007;32(2)
folate? A review of the recent literature on folate supplemen-
tation provides enough information to tentatively answer
The amount of folate needed to help regulate mood, in
terms of intake or serum or red blood cell levels, is not
known. However, folate intake and levels have been stud-
ied extensively in relation to birth defects and plasma ho-
mocysteine levels. Low folate intake or low folate levels are
associated with an increase in birth defects, whereas a meta-
bolic cycle involving folate provides the methyl groups to
methylate homocysteine to methionine. Thus, levels of fo-
late that will minimize birth defects or homocysteine levels
are sufficient to maximize folate function and are probably
appropriate for patients with depression, although different
metabolic systems could possibly be involved. Birth defects
are obviously much more difficult to study than are homo-
cysteine levels, but there is an extensive literature on the
ability of folate supplements to lower homocysteine levels.
A recent metaanalysis looked at the results of 25 random-
ized controlled trials of folate supplements in people who
were not selected because of low folate levels. The conclu-
sion was that daily dosages of 0.8 mg folic acid or more, in
addition to dietary intake, are typically required to achieve
the maximal reduction in plasma homocysteine concentra-
tions (about 25%).17Vitamin B12(0.4 mg/day) produced a
further 7% reduction.
To lower birth defects, mandatory fortification of flour (but
not whole grain flour) with 0.14 mg folate per 100 g of cereal
grain product was introduced in the United States and in
Canada in 1998.18In Chile, the level of fortification is 0.22 mg
folate per 100 g of cereal grain product. In other countries, in-
cluding Austria, Australia, Ireland, Portugal, Spain and the
UK, voluntary fortification has been practised for several
years. In Denmark, Finland and Sweden, fortification is re-
stricted or not allowed.18Compulsory fortification led to an
important decline in birth defects18and a substantial increase
in serum and red blood cell folate levels. However, in the first
few years of this decade, there was a small (16%) decline in
serum folate levels in the United States in spite of continued
fortification.19The reason for this is not clear, but this finding
will help to intensify the debate about whether the amount of
folate added to flour should be increased.18,20,21A recent com-
mentary concluded that, even with the current level of fortifi-
cation, most women are not getting the 0.4 mg of folate per
day that is recommended.21The authors of the metaanalysis
discussed above concluded that, even with fortification of
food at the levels currently used in North America, addi-
tional supplementation with folic acid is likely to lower ho-
mocysteine concentrations by about 15%17; thus levels may
still be suboptimal.
The above results suggest that some people with normal
folate levels, including those who live in countries where
there is voluntary or compulsory fortification of food with fo-
late, may benefit from folate supplementation. Homocysteine
levels can be lowered by folate supplementation, even when
folate levels are normal, so it is not necessarily possible to
distinguish the patients with depression who may benefit
from folate by measuring folate levels. Further, some
subgroups may require more folate than others. For example,
people with the relatively common thermolabile variant of
MTHFR have an elevated incidence of depression and re-
quire higher levels of folate.22,23Given the low cost of folate
tablets (1 mg folic acid tablets can cost less than 5 cents each),
there is no economic reason to avoid giving folate to all pa-
tients with depression, but can folate supplements have any
adverse effects? Several concerns have been raised about the
supplementation of food with folate.18The main concern rele-
vant to the short-term use of folate supplements in depres-
sion patients is the possible masking of vitamin B12deficiency
symptoms. For this reason, it might be prudent to add a vita-
min B12supplement to the folate.
What about the recommendation that 2 mg of folate be
given during the acute, continuation and maintenance treat-
ment of depression?1The actual dosage may be debatable; 1
mg may suffice, particularly in countries where there is vol-
untary or compulsory fortification of food with folate, and
the addition of a vitamin B12supplement may be prudent, but
the general principle is reasonable. With our current knowl-
edge, the potential benefits seem to far outweigh any disad-
vantages. A recent article asked whether folate is “the
ultimate functional food component for disease preven-
tion.”20Although the article didn’t focus on depression, the
question is highly relevant to its treatment.
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Competing interests: None declared.
Rev Psychiatr Neurosci 2007;32(2)
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CANADIAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY
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